IntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor... Show moreIntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. MethodsData were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. ResultsIn participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. ConclusionThis study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). Show less
Objective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with... Show moreObjective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA). Methods: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency <30 minutes and Epworth Sleepiness Scale score >= 10). Participants were randomised 1:1 to solriamfetol (150 mg/day [3 days], then 300 mg/day [4 days]) or placebo for 7 days, before crossover to the other treatment paradigm. On Day 7 of each period, standardised on-road driving tests occurred (2 and 6 hours postdose). Standard deviation of lateral position (SDLP) was the primary endpoint. Results: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia. Conclusions: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA. Show less
Inadequate sleep impairs cognitive function and has been associated with worse academic achievement in higher education students; however, studies that control for relevant background factors and... Show moreInadequate sleep impairs cognitive function and has been associated with worse academic achievement in higher education students; however, studies that control for relevant background factors and include knowledge on sleep hygiene are scarce. This study examined the association of chronic sleep reduction (i.e. symptoms of chronic sleep reduction such as shortness of sleep, sleepiness and irritation), subjective sleep quality and sleep hygiene knowledge with academic achievement (grades and study credits) and study concentration among 1378 higher education students (71% female, mean age 21.73 years, SD = 3.22) in the Netherlands. Demographic, health, lifestyle and study behaviour characteristics were included as covariates in hierarchical regression analyses. After controlling for significant covariates, only chronic sleep reduction remained a significant predictor of lower grades (last exam, average in current academic year). Better sleep quality and sleep hygiene knowledge were associated with better academic achievement, but significance was lost after controlling for covariates, except for a remaining positive association between sleep hygiene beliefs and grades in the current academic year. Moreover, better sleep quality and lower scores on chronic sleep reduction were associated with better study concentration after controlling for significant covariates. To conclude, chronic sleep reduction is associated with academic achievement and study concentration in higher education students. Inadequate sleep hygiene knowledge is moderately associated with worse academic achievement. Future research should investigate whether sleep hygiene interventions improve academic achievement in students of higher education. Show less
Heide, A. van der; Werth, E.; Donjacour, C.E.H.M.; Reijntjes, R.H.A.M.; Lammers, G.J.; Someren, E.J.W. van; ... ; Fronczek, R. 2016
The thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day... Show moreThe thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken 2 times 3g per night for 5 consecutive nights. Both groups underwent 24-h blood sampling and many hormones (prolactin, Growth hormone, melatonin, ghrelin, leptin) were measured and compared before and during SXB treatment. A study using the golden standard on insuline sensitivity is decribed to compare insuline sensitivity between patients and controls, and between patients, before and during satisfactory SXB treatment. ANother study describes body and skintemperature differences between narcolepsy patients and controls. Another chapter describes a rarely described, common feature in narcolepsy, in which patients mistake the memory of a dream for a real experience. In another chapter describes that date of birth is not a risk factor for narcolepsy. Show less
STUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis.... Show moreSTUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones. METHODS:Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night). RESULTS:At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones. CONCLUSIONS:The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion. Show less
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general... Show moreNarcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. Show less
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin)... Show moreNarcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataptexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder. Show less
